The chemical synthesis of peptides and proteins is a widely studied field, and methods have been developed for the syntheses of such compounds using sequential coupling reactions, particularly involving anchoring on solid phases such as polymers. However, sequential synthetic methods are not well suited for the preparation of larger peptides and proteins. For these, segment coupling methods have been developed whereby shorter peptides are joined in a controlled manner to produce larger molecules.
D. S. Kemp and co-workers developed a “thiol capture” strategy for the preparation of large peptides. ((a) Kemp, D. S. Biopolymers 1981, 20, 1793-1804. (b) Kemp D. S.; Carey, R. I. J. Org. Chem. 1993, 58, 2216-2222). This led to additional segment coupling approaches. Among them, the native chemical ligation methodology represents a useful tool for the chemical synthesis of proteins (Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. H. Science 1994, 266, 776-779). In this approach, an N-terminal cysteine residue is required for capturing a peptide thioester as a cysteine thioester of the peptide, which is followed by a spontaneous intramolecular S to N acyl transfer to form the amide (peptide) bond at the ligation junction.
To overcome the restriction imposed by the requirement for a cysteine residue at the ligation site, different strategies have been adopted to extend the repertoire of peptide conjugation techniques: ((a) Beligere, G. S.; Dawson, P. E. J. Am. Chem. Soc. 1999, 121, 6332-6333. (b) Yan, L. Z.; Dawson, P. E. J. Am. Chem. Soc. 2001, 123, 526-533. (c) Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2, 2141-2143. (d) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2, 1939-1941). The use of removable thiol-based auxiliaries is an attractive approach to fulfill the same function as the thiol side chain of the cysteine. Peptides with Nα-linked auxiliaries that can carry out a function analogous to that of cysteine, such as 1-phenyl-2-mercaptoethyl and 2-mercaptobenzyl groups, have been investigated and successfully applied to the synthesis of large peptides: ((a) Canne, L. E.; Bark, S. J.; Kent, S. B. H. J. Am. Chem. Soc. 1996, 118, 5891-5896. (c) Low, D. W.; Hill, M. G.; Carrasco, M. R.; Kent, S. B. H.; Botti, P. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 6554-6559. (d) Offer, J.; Boddy, C.; Dawson, P. E. J. Am. Chem. Soc. 2002, 124, 4642-4646. (e) Macmillan, D.; Anderson, D. W. Org. Len. 2004, 6, 4659-4662. (f) Lu, Y.-A.; Tam, J. P. Org. Lett. 2005, 7, 5003-5006).
The synthesis of glycopeptides from readily available materials represents an advantageous approach to the preparation of higher molecular weight peptides and glycopeptides for structural and functional studies. Therefore, there remains a need for improved methods for the preparation of larger peptides and proteins, glycopeptides, and other peptide derivatives.